Neurochemische Frühdiagnostik und klinische Neuroproteomik demenzieller Erkrankungen

 

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Zusammenfassung

Die vorliegende Arbeit soll eine Übersicht über das sich schnell entwickelnde Gebiet der Neurochemischen Demenzdiagnostik (NDD) geben, wobei der Schwerpunkt auf Anwendungen liegen soll, die zwischenzeitlich bereits Eingang in die Routinediagnostik gefunden haben oder wo dies bald zu erwarten ist. Demenzbiomarker, die in unabhängigen größeren Studien multizentrisch an mehreren tausend Patienten und Probanden validiert wurden, liegen bisher nur für folgende Parameter im lumbalen Liquor vor (liquorbasierte neurochemische Demenzdiagnostik, LiquorNDD): beta-Amyloidpeptide, Gesamt-Tau und hyperphosphorylierte Tau-Proteine (phospho-Tau). Diese Studien belegen eindrucksvoll, dass die CSF-NDD zwischenzeitlich eine hohe Relevanz für die verbesserte Frühund Differenzialdiagnostik demenzieller Erkrankungen erlangt hat und für die Alzheimer-Demenz eine prädiktive Diagnostik bietet.

Summary

This article summarises the current achievements in neurochemical dementia diagnostics (NDD) with special emphasis on applications which have already been introduced into routine diagnostics or which are expected to be introduced shortly. Based on independent multi center studies with several thousands of patients the following neurochemical dementia markers have been validated in cerebrospinal fluid (CSF-NDD): beta-amyloid peptides, total tau and hyperphosphorylated tau proteins (phospho-tau). These studies clearly show that CSF-NDD is of high clinical relevance for the improved early and differential diagnosis of dementias and that it also does offer a diagnostic tool for the predictive diagnosis of incipient Alzheimer’s dementia.

• Literatur

• 1 Andreasen N. et al. Sensitivity, specificity, and stability of CSF-tau in AD in a community-based patient sample. Neurology 1999; 53: 1488-1494.
  CrossrefPubMedGoogle Scholar
• 2 Andreasen N. et al. Evaluation of CSF-tau and CSF-Aß42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol 2001; 58: 373-379.
  PubMedGoogle Scholar
• 3 Arai H. et al. CSF phosphorylated tau protein and mild cognitive impairment: a prospective study. Exp Neurol 2000; 166: 201-203.
  CrossrefPubMedGoogle Scholar
• 4 Arai H. et al. Tau in cerebrospinal fluid: a potential diagnostic marker in Alzheimer’s disease. Ann Neurol 1995; 38: 649-652.
  CrossrefPubMedGoogle Scholar
• 5 Bibl M. et al. CSF amyloid-beta-peptides in Alzheimer’s disease, dementia with Lewy bodies and Parkinson’s disease dementia. Brain 2006; 129: 1177-1187.
  CrossrefPubMedGoogle Scholar
• 6 Bibl M. et al. CSF diagnosis of Alzheimer’s disease and dementia with Lewy bodies. J Neural Transm 2006; 113: 1771-1778.
  CrossrefPubMedGoogle Scholar
• 7 Bibl M. et al. Validation of amyloid-beta peptides in CSF diagnosis of neurodegenerative dementias. Mol Psychiatry. 2007 in Druck.
  PubMedGoogle Scholar
• 8 Bibl M. et al. Reduced CSF carboxyterminally truncated Abeta peptides in frontotemporal lobe degenerations. J Neural Transm 2007; 114: 621-628.
  CrossrefPubMedGoogle Scholar
• 9 Blennow K, Vanmechelen E, Hampel H. CSF total tau, Aß42 and phosphorylated tau protein as biomarkers for Alzheimer’s disease. Mol Neurobiol 2001; 24: 87-97.
  CrossrefPubMedGoogle Scholar
• 10 Blennow K. Cerebrospinal fluid protein biomarkers for Alzheimer’s Disease. Neuro RX 2004; 01: 213-255.
  CrossrefPubMedGoogle Scholar
• 11 Blennow K, Wallin A, Hager O. Low frequency of post-lumbar puncture headache in demented patients. Acta Neurol Scand 1993; 88: 221-223.
  CrossrefPubMedGoogle Scholar
• 12 Blomberg M. et al. Increasing cerebrospinal fluid tau levels in a subgroup of Alzheimer patients with apolipoprotein E allele epsilon 4 during 14 months follow-up. Neurosci Lett 1996; 214: 163-166.
  CrossrefPubMedGoogle Scholar
• 13 Buee L. et al. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 2000; 33: 95-130.
  CrossrefPubMedGoogle Scholar
• 14 Bullock R. New drugs for Alzheimer’s disease and other dementias. Br J Psychiatry 2002; 180: 135-139.
  CrossrefPubMedGoogle Scholar
• 15 Citron M. et al. Evidence that the 42– and 40-amino acid forms of amyloid beta protein are generated from the beta-amyloid precursor protein by different protease activities. Proc Natl Acad Sci USA 1996; 93: 13170-13175.
  CrossrefPubMedGoogle Scholar
• 16 De Jong D. et al. Cerebrospinal Fluid Amyloid b42/Phosphorylated Tau Ratio Discriminates Between Alzheimer’s Disease and Vascular Dementia. J Gerontol A Biol Sci Med Sci 2006; 61: 755-758.
  CrossrefPubMedGoogle Scholar
• 17 De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 2003; 38: 9-12.
  CrossrefPubMedGoogle Scholar
• 18 Farrer LA. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. Jama 1997; 278: 1349-1356.
  CrossrefPubMedGoogle Scholar
• 19 Ferri CP. et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005; 366: 2112-2117.
  CrossrefPubMedGoogle Scholar
• 20 Galasko D. et al. High cerebrospinal fluid tau and low amyloid b42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol 1998; 55: 937-945.
  CrossrefPubMedGoogle Scholar
• 21 Golombowski S. et al. Dependence of cerebrospinal fluid Tau protein levels on apolipoprotein E4 allele frequency in patients with Alzheimer’s disease. Neurosci Lett 1997; 225: 213-215.
  CrossrefPubMedGoogle Scholar
• 22 Grundke-Iqbal I. et al. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986; 83: 4913-4917.
  CrossrefPubMedGoogle Scholar
• 23 Haass C. Take five--BACE and the gamma-secretase quartet conduct Alzheimer’s amyloid betapeptide generation. Embo J 2004; 23: 483-488.
  CrossrefPubMedGoogle Scholar
• 24 Hampel H. et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch Gen Psychiatry 2004; 61: 95-102.
  CrossrefPubMedGoogle Scholar
• 25 Henkel AW. et al. Immune complexes of auto-antibodies against Abeta1-42 peptides patrol cerebrospinal fluid of non-Alzheimer’s patients. Mol Psychiatry 2007; 12: 601-610.
  CrossrefPubMedGoogle Scholar
• 26 Hesse C. et al. Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neurosci Lett 2001; 297: 187-190.
  CrossrefPubMedGoogle Scholar
• 27 Hu YY. et al. Levels of nonphosphorylated and phosphorylated tau in cerebrospinal fluid of Alzheimer’s disease patients : an ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay. Am J Pathol 2002; 160: 1269-1278.
  CrossrefPubMedGoogle Scholar
• 28 Hulstaert F. et al. Improved discrimination of AD patients using b-amyloid₍₁–₄₂₎ and tau levels in CSF. Neurology 1999; 52: 1555-1562.
  CrossrefPubMedGoogle Scholar
• 29 Ida N. et al. Analysis of heterogeneous bA4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay. J Biol Chem 1996; 271: 22908-22914.
  CrossrefPubMedGoogle Scholar
• 30 Iqbal K. et al. Significance and mechanism of Alzheimer neurofibrillary degeneration and therapeutic targets to inhibit this lesion. J Mol Neurosci 2002; 19: 95-99.
  CrossrefPubMedGoogle Scholar
• 31 Iqbal K. et al. Defective brain microtubule assembly in Alzheimer’s disease. Lancet 1986; 02: 421-426.
  Google Scholar
• 32 Itoh N. et al. Large-scale, multicenter study of cerebrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer’s disease. Ann Neurol 2001; 50: 150-156.
  CrossrefPubMedGoogle Scholar
• 33 Kanai M. et al. Longitudinal study of cerebrospinal fluid levels of tau, A beta1–40, and A beta1–42(43) in Alzheimer’s disease: a study in Japan. Ann Neurol 1998; 44: 17-26.
  CrossrefPubMedGoogle Scholar
• 34 Kang J. et al. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987; 325: 733-736.
  CrossrefPubMedGoogle Scholar
• 35 Klafk H. et al. The carboxyl termini of beta-amyloid peptides 1–40 and 1–42 are generated by distinct gamma-secretase activities. J Biol Chem 1996; 271: 28655-28659.
  CrossrefPubMedGoogle Scholar
• 36 Klafki HW. et al. Therapeutic approaches to Alzheimer’s disease. Brain 2006; 129: 2840-2855.
  CrossrefPubMedGoogle Scholar
• 37 Knopman D. Pharmacotheraphy for Alzheimer’s disease. Curr Neurol Neurosci Rep 2001; 01: 428-434.
  CrossrefPubMedGoogle Scholar
• 38 Lammich S. et al. Expression of the Alzheimer protease BACE1 is suppressed via its 5’-untranslated region. EMBO Rep 2004; 05: 620-625.
  CrossrefPubMedGoogle Scholar
• 39 Lewczuk P. et al. Tau Protein Phosphorylated at Threonine 181 in CSF as a Neurochemical Biomarker in Alzheimer’s Disease: Original Data and Review of the Literature. J Mol Neurosci 2004; 23: 115-122.
  CrossrefPubMedGoogle Scholar
• 40 Lewczuk P. et al. Neurochemical diagnosis of Alzheimer’s dementia by CSF Aß42, Aß42/Aß40 ratio and total tau. Neurobiol Aging 2004; 25: 273-281.
  CrossrefPubMedGoogle Scholar
• 41 Mawal-Dewan M. et al. The phosphorylation state of tau in the developing rat brain is regulated by phosphoprotein phosphatases. J Biol Chem 1994; 269: 30981-30987.
  PubMedGoogle Scholar
• 42 Maddalena A. et al. Cerebrospinal Fluid Amyloid b42/Phosphorylated Tau Ratio Discriminates Between Alzheimer’s Disease and Vascular Dementia. Arch Neurol 2003; 60: 1202-1206.
  PubMedGoogle Scholar
• 43 Mayeux R. Evaluation and use of diagnostic tests in Alzheimer’s disease. Neurobiol Aging 1998; 19: 139-143.
  CrossrefPubMedGoogle Scholar
• 44 Mayeux R. et al. Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer’s disease. Alzheimer’s Disease Centers Consortium on Apolipoprotein E and Alzheimer’s Disease. N Engl J Med 1998; 338: 506-511.
  Google Scholar
• 45 Motter R. et al. Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 1995; 38: 643-648.
  CrossrefPubMedGoogle Scholar
• 46 Mulder C. et al. Genetic and biochemical markers for Alzheimer’s disease: recent developments. Ann Clin Biochem 2000; 37: 593-607.
  CrossrefPubMedGoogle Scholar
• 47 Otto M. et al. Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurosci Lett 1997; 225: 210-212.
  CrossrefPubMedGoogle Scholar
• 48 Panegyres PK. The amyloid precursor protein gene: a neuropeptide gene with diverse functions in the central nervous system. Neuropeptides 1997; 31: 523-535.
  CrossrefPubMedGoogle Scholar
• 49 Parnetti L. et al. CSF phosphorylated tau is a possible marker for discriminating Alzheimer’s disease from dementia with Lewy bodies. Phospho-Tau International Study Group. Neurol Sci 2001; 22: 77-78.
  Google Scholar
• 50 Reiber H. Dynamics of brain-derived proteins in cerebrospinal fluid. Clin Chim Acta 2001; 310: 173-186.
  CrossrefPubMedGoogle Scholar
• 51 Riemenschneider M. et al. Cerebrospinal betaamyloid₍₁–₄₂₎ in early Alzheimer’s disease: association with apolipoprotein E genotype and cognitive decline. Neurosci Lett 2000; 284: 85-88.
  CrossrefPubMedGoogle Scholar
• 52 Rosner H. et al. Developmental expression of tau proteins in the chicken and rat brain: rapid downregulation of a paired helical filament epitope in the rat cerebral cortex coincides with the transition from immature to adult tau isoforms. Int J Dev Neurosci 1995; 13: 607-617.
  CrossrefPubMedGoogle Scholar
• 53 Schoonenboom NS. et al. Amyloid beta (1–42) and phosphorylated tau in CSF as markers for earlyonset Alzheimer disease. Neurology 2004; 62: 1580-1584.
  CrossrefPubMedGoogle Scholar
• 54 Shahani N, Brandt R. Functions and malfunctions of the tau proteins. Cell Mol Life Sci 2002; 59: 1668-1680.
  CrossrefPubMedGoogle Scholar
• 55 Sjögren M. et al. Low cerebrospinal fluid b-amyloid 42 in patients with acute bacterial meningitis and normalization after treatment. Neurosci Lett 2001; 314: 33-36.
  CrossrefPubMedGoogle Scholar
• 56 Strittmatter WJ. et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 1993; 90: 1977-1981.
  CrossrefPubMedGoogle Scholar
• 57 Strittmatter WJ. et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA 1993; 90: 8098-8102.
  CrossrefPubMedGoogle Scholar
• 58 Sunderland T. et al. Decreased beta-amyloid1–42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. Jama 2003; 289: 2094-2103.
  PubMedGoogle Scholar
• 59 The Working Group on: “Molecular and Biochemical Markers of Alzheimer’s Disease”. Consensus report of the Working Group on: “Molecular and Biochemical Markers of Alzheimer’s Disease”. The Ronald and Nancy Reagan Research Institute of the Alzheimer’s Association and the National Institute on Aging Working Group. Neurobiol Aging 1998; 19: 109-116.
  Google Scholar
• 60 Vanmechelen E. et al. CSF-Phospho-tau (181P) as a Promising Marker for Discriminating Alzheimer’s Disease from Dementia with Lewy Bodies. In Alzheimer’s Disease: Advances in Etiology, Pathogenesis and Therapeutics. Iqbal K, Sisodia SS, Winblad B. (eds.) Chichester: John Wiley and Sons Ltd; 2001: 285-291.
  Google Scholar
• 61 Vassar R. et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999; 286: 735-741.
  CrossrefPubMedGoogle Scholar
• 62 Wiltfang J. et al. Amyloid beta peptide ratio 42/40 but not A beta 42 correlates with phospho-Tau in patients with lowand high-CSF A beta 40 load. J Neurochem 2007; 101: 1053-1059.
  CrossrefPubMedGoogle Scholar
• 63 Wiltfang J. et al. Highly conserved and diseasespecific patterns of carboxyterminally truncated Aß peptides 1–37/38/39 in addition to 1-40/42 in Alzheimer’s disease and in patients with chronic neuroinflammation. J Neurochem 2002; 81: 481-496.
  CrossrefPubMedGoogle Scholar
• 64 Wiltfang J. et al. Elevation of b-amyloid peptide 2–42 in sporadic and familial Alzheimer’s disease and its generation in PS1 knockout cells. J Biol Chem 2001; 27: 42645-42657.
  Google Scholar
• 65 Wiltfang J. et al. Molecular biology of Alzheimer’s dementia and its clinical relevance to early diagnosis and new therapeutic strategies. Gerontology 2001; 47: 65-71.
  CrossrefPubMedGoogle Scholar
• 66 Wiltfang J. et al. β-amyloid peptides in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Ann Neurol 2003; 54: 263-267.
  CrossrefPubMedGoogle Scholar
• 67 Wiltfang J. et al. Consensus paper of the WFSBP Task Force on Biological Markers of Dementia: the role of CSF and blood analysis in the early and differential diagnosis of dementia. World J Biol Psychiatry 2005; 06: 69-84.
  CrossrefPubMedGoogle Scholar
• 68 Wiltfang J. et al. Isoform pattern of 14–3–3 proteins in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. J Neurochem 1999; 73: 2485-2490.
  PubMedGoogle Scholar
• 69 Zerr I. et al. Detection of 14–3–3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease. Ann Neurol 1998; 43: 32-40.
  CrossrefPubMedGoogle Scholar